Project Summary/Abstract The standard therapy for malignant primary bone tumors such as osteosarcoma and chondrosarcoma involves major surgeries. For tumors located in difficult regions such as the pelvis, surgical intervention could lead to serious side effects. These include loss of a limb and/or function, loss of bowel, bladder and sexual function as well as problems with wound healing and surgical complications. Therefore, exploring other approaches that can improve or complement current surgical techniques is important. Our long term goal is to find new ways to increase the efficacy of treatment for primary bone tumors. Radiation therapy is an excellent local control alternative but primary bone tumors are resistant except for Ewing?s sarcoma. Preliminary work in our laboratory shows that small molecule DNA repair inhibitors are effective at radiosensitizing primary bone tumor cells. Additionally, gold nanoparticles (AuNPs) are shown to enhance radiosensitivity by increasing the physical local dose of radiation inside tumors. While these separate observations are well known in the literature, there appears to be lack of studies that combine these two agents to investigate whether their combination leads to synergistic radiosensitization. Also, the underlying mechanism of how this strategy might work remains to be studied. Our central hypothesis is that combination of DNA repair inhibition and AuNPs provides synergistic sensitizing effects through independent mechanisms with AuNPs increasing levels of damage induction and DNA repair inhibitor preventing repair. In Aim 1, we will investigate the efficacy of combining a DNA repair inhibitor with AuNPs to radiosensitize primary bone tumors. We will perform both in vitro and in vivo studies to determine the effects of the combination therapy. In Aim 2, we will investigate the DNA damage response activated when combining radiation therapy with a DNA repair inhibitor and AuNPs. We will explore the levels of key effectors activated in response to the DNA damage caused by the combination therapy and examine downstream effects on DNA repair, cell cycle and apoptosis. The results of this study will pave the way for the treatment of primary bone tumors with radiation therapy. This will lead to a new approach that could complement surgery and improve survival and quality of life. Our finding could also lead to new scientific insight regarding the mechanism of action for a combination radiosensitization strategy that uses both a biological and physical approach.